Pacing-based hypertension therapy safety

ABSTRACT

This document discusses, among other things, systems and methods to generate a first pacing waveform during a first pacing period and a second pacing waveform during a second pacing period, and alternate the first and second pacing periods to provide pacing-based hypertension therapy to a heart of a patient to reduce patient blood pressure, wherein the first pacing waveform has a first atrioventricular (AV) delay and the second pacing waveform has a second AV delay longer than the first AV delay. Physiologic information can be received from the patient, and one of the first or second pacing period for delivery to the patient can be determined using the received physiologic information.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Provisional Patent Application Ser. No. 62/685,454, filed onJun. 15, 2018, and U.S. Provisional Patent Application Ser. No.62/650,260, filed on Mar. 29, 2018, each of which is herein incorporatedby reference in its entirety.

TECHNICAL FIELD

This document relates generally to medical devices, and moreparticularly, but not by way of limitation, to systems, devices, andmethods for pacing-based hypertension therapy safety.

BACKGROUND

Blood pressure is the pressure of circulating blood on the walls ofblood vessels, and typically refers to the pressure in large arteries ofthe systemic system. When further specified, such as left ventricular(LV) pressure, etc., such pressure refers to the pressure in thatphysiologic component. Blood pressure is commonly expressed in terms ofsystolic pressure, the pressure during a heart contraction, anddiastolic pressure, the pressure between heart contractions, eachmeasured in millimeters of mercury (mmHg).

High blood pressure, or hypertension (HTN), is a risk factor formortality, as well as other adverse medical events, including, forexample, heart failure (HF), ischemia, arrhythmia, stroke, acute cardiacdecompensation, organ failure, etc. High blood pressure can also beasymptomatic, where patients don't appreciate their condition until anadverse medical event occurs. Accordingly, it is important to monitorblood pressure information, such as to monitor or assess patientcondition or status, including worsening or recovery of one or morephysiologic conditions, or to supplement other detections ordeterminations. Moreover, it is important to reduce blood pressure.

SUMMARY

This document discusses, among other things, systems and methods togenerate a first pacing waveform during a first pacing period and asecond pacing waveform during a second pacing period, and alternate thefirst and second pacing periods to provide pacing-based hypertensiontherapy to a heart of a patient to reduce patient blood pressure,wherein the first pacing waveform has a first atrioventricular (AV)delay and the second pacing waveform has a second AV delay longer thanthe first AV delay. Physiologic information can be received from thepatient, and one of the first or second pacing period for delivery tothe patient can be determined using the received physiologicinformation.

An example (e.g., “Example 1”) of subject matter (e.g., a system) mayinclude: a stimulation circuit configured to generate a first pacingwaveform during a first pacing period and a second pacing waveformduring a second pacing period, and to alternate the first and secondpacing periods to provide pacing-based hypertension therapy to a heartof a patient to reduce patient blood pressure, wherein the first pacingwaveform has a first atrioventricular (AV) delay and the second pacingwaveform has a second AV delay longer than the first AV delay; a signalreceiver circuit configured to receive physiologic information from thepatient; and an assessment circuit configured to determine one of thefirst or second pacing period for delivery to the patient using thereceived physiologic information.

In Example 2, the subject matter of Example 1 may optionally beconfigured such that the assessment circuit is configured to adjust thefirst or second pacing period using the received physiologicinformation.

In Example 3, the subject matter of any one or more of Examples 1-2 mayoptionally be configured such that the assessment circuit is configuredto detect a patient condition using the received physiologicinformation, and to discontinue the first pacing period in response to adetected worsening patient condition.

In Example 4, the subject matter of any one or more of Examples 1-3 mayoptionally be configured such that the assessment circuit is configuredto detect an arrhythmia of the patient using the received physiologicinformation, and to discontinue the first pacing period in response to anumber of detected arrhythmias over a threshold time period.

In Example 5, the subject matter of any one or more of Examples 1-4 mayoptionally be configured such that the assessment circuit is configuredto determine an arrhythmia metric of the patient using the receivedphysiologic information, and to adjust the first or second pacing periodusing the determined arrhythmia metric.

In Example 6, the subject matter of any one or more of Examples 1-5 mayoptionally be configured such that the assessment circuit is configuredto determine a heart failure metric of the patient using the receivedphysiologic information, and to adjust the first or second pacing periodusing the determined heart failure metric.

In Example 7, the subject matter of any one or more of Examples 1-6 mayoptionally be configured such that the signal receiver circuit isconfigured to receive third heart sound (S3) information and fourthheart sound (S4) information from the patient, and the assessmentcircuit is configured to determine an indication of early-to-lateventricular-filling velocities (E/A ratio) using the S3 information andthe S4 information, and to adjust the first or second pacing periodusing the determined E/A ratio.

In Example 8, the subject matter of any one or more of Examples 1-7 mayoptionally be configured such that the signal receiver circuit isconfigured to receive first heart sound (S1) information from thepatient, and the assessment circuit is configured to determine anindication of long-term impact of the first pacing period to the patientusing S1 information detected during the second pacing period, and toadjust the first or second pacing period using the determined indicationof long-term impact.

In Example 9, the subject matter of any one or more of Examples 1-8 mayoptionally be configured such that the signal receiver circuit isconfigured to receive first heart sound (S1) information and secondheart sound (S2) information from the patient, and the assessmentcircuit is configured to determine an S1 metric and an S2 metric for thepatient over the first and second pacing periods, and to adjust thefirst or second pacing periods to reduce the S2 metric without reducingthe S1 metric.

In Example 10, the subject matter of any one or more of Examples 1-9 mayoptionally be configured such that the assessment circuit is configuredto, in response to the determined first or second pacing period, providean indication to a user to adjust the pacing-based hypertension therapyto the patient.

An example (e.g., “Example 11”) of subject matter (e.g., at least onemachine-readable medium) may include instructions that, when performedby a medical device, cause the medical device to: generate a firstpacing waveform during a first pacing period and a second pacingwaveform during a second pacing period, and alternate the first andsecond pacing periods to provide pacing-based hypertension therapy to aheart of a patient to reduce patient blood pressure, wherein the firstpacing waveform has a first atrioventricular (AV) delay and the secondpacing waveform has a second AV delay longer than the first AV delay;receive physiologic information from the patient; and determine one ofthe first or second pacing period for delivery to the patient using thereceived physiologic information.

In Example 12, the subject matter of Example 11 may optionally beconfigured such that the instructions, when performed by the medicaldevice, cause the medical device to: adjust the first or second pacingperiod using the received physiologic information.

In Example 13, the subject matter of any one or more of Examples 11-12may optionally be configured such that the instructions, when performedby the medical device, cause the medical device to: detect a patientcondition using the received physiologic information; and discontinuethe first pacing period in response to a detected worsening patientcondition.

In Example 14, the subject matter of any one or more of Examples 11-13may optionally be configured such that the instructions, when performedby the medical device, cause the medical device to: detect an arrhythmiaof the patient using the received physiologic information; anddiscontinue the first pacing period in response to a number of detectedarrhythmias over a threshold time period.

In Example 15, the subject matter of any one or more of Examples 11-14may optionally be configured such that the instructions, when performedby the medical device, cause the medical device to: determine anarrhythmia metric of the patient using the received physiologicinformation, and to adjust the first or second pacing period using thedetermined arrhythmia metric.

An example (e.g., “Example 16”) of subject matter (e.g., a method) mayinclude: generating, using a stimulation circuit, a first pacingwaveform during a first pacing period and a second pacing waveformduring a second pacing period, and alternating the first and secondpacing periods to provide pacing-based hypertension therapy to a heartof a patient to reduce patient blood pressure, wherein the first pacingwaveform has a first atrioventricular (AV) delay and the second pacingwaveform has a second AV delay longer than the first AV delay;receiving, using a signal receiver circuit, physiologic information fromthe patient; and determining, using an assessment circuit, one of thefirst or second pacing period for delivery to the patient using thereceived physiologic information.

In Example 17, the subject matter of Example 16 may optionally beconfigured to include adjusting, using the assessment circuit, the firstor second pacing period using the received physiologic information.

In Example 18, the subject matter of any one or more of Examples 16-17may optionally be configured to include: detecting, using the assessmentcircuit, a patient condition using the received physiologic information;and discontinuing the first pacing period in response to a detectedworsening patient condition.

In Example 19, the subject matter of any one or more of Examples 16-18may optionally be configured to include: detecting, using the assessmentcircuit, an arrhythmia of the patient using the received physiologicinformation; and discontinuing the first pacing period in response to anumber of detected arrhythmias over a threshold time period.

In Example 20, the subject matter of any one or more of Examples 16-19may optionally be configured to include: determining, using theassessment circuit, an arrhythmia metric of the patient using thereceived physiologic information; and adjusting, using the assessmentcircuit, the first or second pacing period using the determinedarrhythmia metric.

An example (e.g., “Example 21”) of subject matter (e.g., a system orapparatus) may optionally combine any portion or combination of anyportion of any one or more of Examples 1-20 to include “means for”performing any portion of any one or more of the functions or methods ofExamples 1-20, or a “non-transitory machine-readable medium” includinginstructions that, when performed by a machine, cause the machine toperform any portion of any one or more of the functions or methods ofExamples 1-20.

This summary is intended to provide an overview of subject matter of thepresent patent application. It is not intended to provide an exclusiveor exhaustive explanation of the disclosure. The detailed description isincluded to provide further information about the present patentapplication. Other aspects of the disclosure will be apparent to personsskilled in the art upon reading and understanding the following detaileddescription and viewing the drawings that form a part thereof, each ofwhich are not to be taken in a limiting sense.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsmay describe similar components in different views. Like numerals havingdifferent letter suffixes may represent different instances of similarcomponents. The drawings illustrate generally, by way of example, butnot by way of limitation, various embodiments discussed in the presentdocument.

FIGS. 1A and 1B illustrate example relationships of systolic bloodpressure measurements at different pacing patterns.

FIG. 2 illustrates an example system including an ambulatory medicaldevice (AMD) configured to sense or detect information from a patient.

FIG. 3 illustrates an example system (e.g., a medical device, etc.)including a signal receiver circuit and an assessment circuit.

FIG. 4 illustrates an example system including an ambulatory medicaldevice (AMD) coupled to an external or remote system, such as anexternal programmer.

FIG. 5 illustrates an example of a Cardiac Rhythm Management (CRM)system and portions of an environment in which the CRM system canoperate.

FIG. 6 illustrates an example method to determine an adjustedatrioventricular (AV) delay using determined first and secondphysiologic parameters.

FIG. 7 illustrates an example method to determine a pacing period usingreceived physiologic information.

FIG. 8 illustrates an example method to determine an adjustedpacing-based hypertension parameter using received patient metabolicdemand information.

FIG. 9 illustrates an example method to determine an increased pacingrate for a pacing period using a first AV delay.

FIG. 10 illustrates a block diagram of an example machine upon which anyone or more of the techniques (e.g., methodologies) discussed herein mayperform.

DETAILED DESCRIPTION

Pacing-based hypertension (HTN) therapy has developed for patientshaving implanted dual-chamber pacemakers with transvenous leads, wherealternating periods of pacing at shorter and longer atrioventricular(AV) delay intervals has been shown to reduce blood pressure and thushelp with hypertension. Pacing at a shortened AV delay interval (e.g.,20-80 ms) in contrast to a normal or longer AV delay interval (e.g.,100-180 ms) can reduce ventricular filling time, stroke volume andaccordingly, arterial pressure. However, over time, such reductions maytrigger a baroreflex response, increasing total peripheral resistance(TPR), and eventually increasing blood pressure towards its originallevel. Transitioning between periods of shorter and longer AV delayintervals can modulate the baroreflex response of the patient,preventing an increase in pressure by activation of the autonomicnervous system (ANS). Patterned-pacing-based HTN therapy can includeinterjecting longer AV delay intervals (e.g., 1-3 beats of normal orlonger AV delay intervals) within the reduced AV delay periods (e.g.,every 8-12 beats of shortened AV delay intervals) can further modulatethe baroreflex response of the patient, further reducing transientsafter transitions, and drift between transitions.

FIGS. 1A and 1B illustrate example relationships 100, 101 of systolicblood pressure measurements 102, 103 at different pacing patterns. InFIG. 1A, a first transition 104 in a pacing-based HTN therapy marks achange from a longer AV delay period (e.g., 140 ms AV delay intervals)to a shortened AV delay period (e.g., 40 ms AV delay intervals), wherethe systolic blood pressure 102 drops (e.g., from 150 mmHg to 100 mmHg)before rising to a level near the original pressure measurement. Asecond transition 106 marks a change from the shortened AV delay period(between first and second transitions 104, 106) back to the longer AVdelay period (before and after the first and second transitions 104,106), which causes a spike in the systolic blood pressure, then a returntowards the baseline.

In FIG. 1B, a first transition 105 in a pattern-pacing-based HTN therapymarks a change from a longer AV delay (e.g., 140 ms) to a repeatingsequence of 10 shortened AV delay (e.g., 40 ms) beats and 2 longer AVdelay beats, and a second transition 107 marks a change from therepeating sequence in the shortened AV delay period (between first andsecond transitions 105, 107) to the longer AV delay period (before andafter the first and second transitions 105, 107). In contrast to FIG.1A, there are no significant drops or spikes in systolic blood pressure103 after the first or second transition 105, 107, or significantlydrift between the first and second transitions 105, 107, in the exampleillustrated in FIG. 1B.

The present inventors have recognized, among other things, improvementsto pacing-based or pattern-pacing-based HTN therapy configured toincrease safety or control, reduce detrimental impact, or improvecardiac function associated with the pacing-based HTN therapy, such asthrough assessment of physiologic information (e.g., heart soundinformation, etc.), and not rigid adherence to a predefined pattern orrange. Such improvements allow the pacing-based or pattern-pacing-basedHTN therapy to be optimized for each patient in a population, providinga greater benefit to the patient, and improved device function.

Ambulatory medical devices, including implantable, leadless, or wearablemedical devices configured to monitor, detect, or treat various cardiacconditions associated with a reduced ability of a heart to sufficientlydeliver blood to a body, such as heart failure (HF), arrhythmias,hypertension, etc. Various ambulatory medical devices can be implantedin a patient's body or otherwise positioned on or about the patient tomonitor patient physiologic information, such as heart sounds,respiration (e.g., respiration rate, tidal volume, etc.), impedance(e.g., thoracic impedance), pressure, cardiac activity (e.g., heart rate(HR)), physical activity, posture, or one or more other physiologicparameters of a patient, or to provide electrical stimulation or one ormore other therapies or treatments to optimize or control contractionsof the heart.

Traditional cardiac rhythm management (CRM) devices, such as pacemakers,defibrillators, or cardiac monitors, include implanted devices (e.g.,implantable cardioverter-defibrillators (ICDs), etc.), subcutaneousdevices (e.g., subcutaneous ICDs (S-ICDs), etc.), or one or more otherdevices configured to be implanted within in a chest of a patient, orunder the skin of the patient, in certain examples, having one or moreleads to position one or more electrodes or other sensors at variouslocations in the heart, such as in one or more of the atria orventricles. Separate from, or in addition to, the one or more electrodesor other sensors of the leads, the CRM device can include one or moreelectrodes or other sensors (e.g., a pressure sensor, an accelerometer,a gyroscope, a microphone, etc.) powered by a power source in the CRMdevice. The one or more electrodes or other sensors of the leads, theCRM device, or a combination thereof, can be configured detectphysiologic information from, or provide one or more therapies orstimulation to, the patient, for example, using one or more stimulationcircuits.

Leadless cardiac pacemakers (LCP) include small (e.g., smaller thantraditional implantable CRM devices), self-contained devices configuredto detect physiologic information from or provide one or more therapiesor stimulation to the heart without traditional lead or implantable CRMdevice complications (e.g., required incision and pocket, complicationsassociated with lead placement, breakage, or migration, etc.). Incertain examples, an LCP can have more limited power and processingcapabilities than a traditional CRM device; however, multiple LCPdevices can be implanted in or about the heart to detect physiologicinformation from, or provide one or more therapies or stimulation to,one or more chambers of the heart. The multiple LCP devices cancommunicate between themselves, or one or more other implanted orexternal devices.

Wearable or external medical sensors or devices can be configured todetect or monitor physiologic information of the patient withoutrequired implant or an in-patient procedure for placement, batteryreplacement, or repair. However, such sensors and devices, in contrastto implantable, subcutaneous, or leadless medical devices, may havereduced patient compliance, increased detection noise, or reduceddetection sensitivity.

Determination of one or more patient conditions (e.g., hypertension, HF,etc.), or risk stratification for one or more patient conditions, oftenrequires some initial assessment time to establish a baseline level orcondition from one or more sensors or physiologic information from whicha detected deviation is indicative of the patient condition, or risk ofpatient condition or future adverse medical event (e.g., the risk of thepatient experiencing a heart failure event (HFE) within a followingperiod, etc.). Changes in physiologic information can be aggregated andweighted based on one or more patient-specific stratifiers. However,such changes and risk stratification are often associated with one ormore thresholds, for example, having a clinical sensitivity andspecificity across a target population with respect to a specificcondition (e.g., HF), etc., and one or more specific time periods, suchas daily values, short-term averages (e.g., daily values aggregated overa number of days), long-term averages (e.g., daily values aggregatedover a number of short-term periods or a greater number of days(sometimes different days than used for the short-term average)), etc.

For example, a multisensor algorithm has been demonstrated to predict HFevents in patients with a high sensitivity and low false positive rateusing physiologic information detected from one or more implanted orambulatory medical devices. In other examples, such algorithm can beapplied to one or more other medical events, such as hypertension or oneor more conditions associated with hypertension, etc. The multisensoralgorithm can determine a composite physiologic parameter using one ormore of the following physiologic information: heart sounds (e.g., afirst heart sound (S1), a second heart sound (S2), a third heart sound(S3), a fourth heart sound (S4), heart-sounds related time intervals,etc.), thoracic impedance (TI), respiratory rate (RR), rapid shallowbreathing index (RSBI), heart rate (HR) (e.g., nighttime HR), activity,posture, cardiac activity, pressure, etc.

In certain examples, such multisensor algorithm can be adjusted using adetermined patient risk level (e.g., a stratifier). The combination ofor weight of respective primary and secondary sensors used to determinethe composite physiologic parameter can be adjusted using the determinedpatient risk level. For example, if the determined patient risk levelindicates a low risk of a worsening physiologic condition, the compositephysiologic parameter can be determined using one or more primarysensors (and not one or more secondary sensors). If the determinedpatient risk level indicates a medium or high risk of worsening heartfailure, the composite physiologic parameter can be determined using theprimary sensors and a combination of the secondary sensors, depending onthe determined patient risk level.

FIG. 2 illustrates an example system 200 including an ambulatory medicaldevice (AMD) 202 configured to sense or detect information from apatient 201. In an example, the AMD 202 can include an implantablemedical device (IMD), a subcutaneous or leadless medical device, awearable or external medical device, or one or more other implantable orexternal medical devices or patient monitors. The AMD 202 can include asingle device, or a plurality of medical devices or monitors configuredto detect patient information.

The AMD 202 can include one or more sensors configured to receivephysiologic information of a patient 201. In an example, the AMD 202 caninclude one or more of a respiration sensor 204 configured to receiverespiration information (e.g., a respiration rate (RR), a respirationvolume (tidal volume), etc.), a heart sound sensor 206 configured toreceive heart sound information, an impedance sensor 208 (e.g.,intrathoracic impedance sensor, transthoracic impedance sensor, etc.)configured to receive impedance information, a cardiac sensor 210configured to receive cardiac electrical information, an activity sensor212 configured to receive information about a physical motion (e.g.,activity, steps, etc.), a posture sensor 214 configured to receiveposture or position information, a pressure sensor 216 configured toreceive pressure information, or one or more other sensors configured toreceive physiologic information of the patient 201.

One or more of the sensors in the AMD 210 may include existingphysiologic sensors. However, using the system and methods describedherein, the sensitivity and specificity of one or more metricsassociated with a risk of worsening heart failure (HF) detected usingexisting sensors can be increased without otherwise increasing systemcost or power, or negatively affecting usable battery life of theexisting sensors.

Safety

The present inventors have recognized, among other thing, that rightventricle (RV) pacing, such as continuous RV pacing, can lead topacing-induced heart failure (HF), such as ventricular dyssynchrony(e.g., interventricular asynchrony, intraventricular asynchrony, etc.).In certain examples, dyssynchrony can lead to an enlarged heart thatmust work harder to provide required cardiac output due to uncoordinatedcontractions.

In an example, a composite physiological parameter can be used tomonitor a patient for worsening HF or one or more other physiologicconditions. The composite physiological parameter can be adjusted by astratifier, such as described above. In certain examples, S3 can berelated to filling pressure—an increase in S3 amplitude, morphology, orenergy (e.g., an integral or RMS value of S3 over an S3 window, incertain examples, determined with respect to one or more other heartsounds, such as S2, or cardiac activity, such as one or more cardiacfeatures (e.g., R-wave, etc.), heart rate, etc.) can be indicative of anincrease in filling pressure. An increase in filling pressure can beindicative of HF. In other examples, an increase in S3 (e.g., >1 mG, ifmeasured with an accelerometer), respiration rate trending (RRT)(e.g., >20 BPM), or an increase in RRT variability (e.g., max−min>4 bpm)can be indicative of HF.

In an example, one or both of the composite physiological parameter orthe stratifier can include or be substantially based on the S3amplitude, morphology, energy, a differential between two S3 valuestaken at different times or over different intervals (e.g., short-termaverage (or median or one or more other values) versus long-term average(or medium or one or more other values), having overlapping ornon-overlapping windows, etc.), or an S3 value normalized with one ormore other measures (e.g., S1 (related to contractility, inotropy,cannon-wave back pressure, etc.), S2 (related to blood pressure in theaorta, ejection fraction, etc.), S3 (e.g., fluid backup, etc.), S4,etc.). In an example, S2/S1, S3/S1, S3/S4, or one or more othernormalized heart sound values can be used, or one or more other valuesnormalized by a heart sound (e.g., S3). In other examples, one or moreother heart sounds can be determined.

In certain examples, S4 can be detected without coordinating or liningup the electrical cardiac activity to accelerometer information used todetermine heart sounds, etc. The ratio of S3/S4 can be used as asurrogate for the ratio of early (E) to late (A) ventricular fillingvelocities (E/A ratio). The E/A ratio can be used, alone or incombination with other physiologic parameters, to determine a possiblerisk of adverse outcome of pacing-based or pattern-pacing-based HTNtherapy. For example, during therapy, if S1 is high (e.g., at or above abaseline level (e.g., 2 mG, etc.) or increasing relative to a previousS1 level or to an S1 level outside of therapy (e.g., 10% higher than anS1 level outside of therapy, etc.), indicative of a threshold amount ofventricular filling and contraction), therapy can continue. If S1 is low(e.g., below a baseline level or decreasing relative to a previous S1level or to an S1 level outside of therapy (e.g., 10% lower than an S1level outside of therapy, etc.)), a ratio of S3/S4 can be determined. Ifthe ratio of S3/S4 is low and S3 is low (e.g., below baseline levels(e.g., an S3/S4 ratio below 0.8, etc., or an S3 level below 1 mG, etc.)or decreasing relative to previous levels or previous levels outside oftherapy, indicative of less ventricular filling and a smaller amount offilling from passive ventricular filling), pacing-based orpattern-pacing-based HTN therapy may proceed, though with caution, whilemonitoring for changes (e.g., chronic changes in absolute or relativelevels) in S1 or S3. If the ratio of S3/S4 ratio is low and S3 is high(e.g., with respect to baseline levels or relative to previous levels orprevious levels outside of therapy, indicative of less filling but asignificant portion of which comes from atrial kick), pacing-based orpattern-pacing-based HTN therapy can be discontinued.

Thus, one or more of pacing-based or pattern-pacing-based HTN therapycan be adjusted, reduced, or discontinued using an increase in detectedS3 (or one or more other heart sound parameters), or an increase in acomposite physiological parameter (or stratifier) determined using, orbased on, S3 (or one or more other heart sound parameters). For example,a significant increase in S3 (e.g., relative to a previous value, suchas a 20% increase, etc.), may indicate that LV filling pressure hasincreased and not enough blood has been cleared from pulmonarycirculation, and that pacing-based or pattern-pacing-based HTN therapyshould be discontinued. In other examples, pacing-based orpattern-pacing-based HTN therapy can be adjusted, reduced, ordiscontinued to maintain or reduce an S3 value, or a compositephysiological value or stratifier determined using or based on an S3value (or one or more other heart sound parameters). In other examples,a diminishing S2 relative to an S2 level outside of therapy or relativeto intrinsic beats at the start of therapy can indicate an effectivetherapy. Accordingly, pacing-based or pattern-pacing-based HTN therapycan be adjusted to maintain S1, but diminish S2. In an example, one ormore other physiologic parameters can be used, alone, in combinationwith one or more other parameters (e.g., S3, S4, etc.), or as part of acomposite physiologic parameter or stratifier, to adjust or provide atherapy.

In other examples, one or more heart sound parameters can be used todetermine if hypotension occurs during therapy. For example, bloodpressure can be detected using S2 in the absence of substantive changesin S1 indicative of contractility changes. In other examples, one ormore other types of information can be used to determine if the patienthas fallen, or is suffering from low blood pressure, such as identifyingaccelerometer or activity data indicative of gate changes, falls,decreases in activity, or one or more other indications of low bloodpressure. If hypotension is determined, the pacing-based orpattern-pacing-based HTN therapy can be discontinued. In other examples,upon determination of hypotension, the pacing rate, AV delay value, orone or more other pacing parameters can be adjusted to increase bloodpressure. For example, using one or more Frank-Starling relationships, apacing parameter can be adjusted to increase blood pressure (e.g.,increasing filling time, etc.). Moreover, such relationships can bedetected, and parameters controlled, using heart sound information.

In certain examples, in patients without significant atrial kick, anamount of atrial filling must occur before activation to providesufficient cardiac output. Such patients may not tolerate a shortened AVdelay. In certain examples, diastolic filling parameters and atrial kickcan be detected using heart sounds. For example, an increase in S1 canbe indicative of an increased diastolic filling, and a decrease in S1can be indicative of a decreased diastolic filling. In another example,an S2-R or an S4-R interval may be used to quantify diastolic fillingtime. Patients with S2-R intervals below a threshold (e.g., <300 msec)may not be good candidates for pacing-based or pattern-based therapy,due to a lack of passive filling. In such cases, active filling time maybe more beneficial than maintaining metabolic demand. Such measures canbe monitored during therapy as a safety precaution.

Further, atrial kick can be detected using S4. In other examples,physiologic information can be monitored to detect retrograde conductionor changes to an intrinsic P-R interval, related to diastolic fillingtime. Further, identifying a split S1 or a split S2 may indicate that apatient may not tolerate a shortened AV delay. Patients can be screenedprior to pacing-based or pattern-pacing-based HTN therapy using adetected or identified split S1 or split S2. In other examples,pacing-based or pattern-pacing-based HTN therapy can be adjusted,reduced, or discontinued using a detected atrial kick, split S1 or splitS2, or detected diastolic filling parameters. In an example,pacing-based or pattern-pacing-based HTN therapy can be intermittentlysuspended, with one or more heart sound measurements taken during thebreak in therapy (e.g., during a time with longer AV delay intervals,etc.). For example, S1 measurements, or a composite physiologicalparameter or stratifier can be determined using or based on S1, can bedetermined to evaluate a long-term impact of pacing-based orpattern-pacing-based HTN therapy. For example, S1 can be used to providean indication of cardiac contractility. A significant drop in S1 (e.g.,relative to previous levels) may indicate a reduction in contractility.If S1 cannot be maintained or increased, pacing-based orpattern-pacing-based can be discontinued.

In other examples, pacing-based or pattern-pacing-based HTN therapy,transitioning between a longer AV delay interval and a shortened AVdelay interval, or pacing with shortened AV delay intervals may lead toarrhythmias. Accordingly, a composite physiologic parameter, stratifier,or other physiologic parameter can be monitored to reduce number oftransitions between longer AV delay intervals and shortened AV delayintervals to provide a desired blood pressure decrease, thereby reducingthe risk of arrhythmias. Further, physiologic information can bemonitored for signs of arrhythmias, such as premature contractions(PACs), atrial arrhythmia burden, or one or more other arrhythmias.Pacing-based or pattern-pacing-based HTN therapy can be adjusted,reduced, or discontinued using a number of detected arrhythmias within acertain time period.

In an example, instead of pacing at the RV, pacing-based orpattern-pacing-based HTN therapy can be implemented using His-bundlepacing, such as providing a pacing pulse configured to activate the Hisbundle, bundle branches, or Purkinje fibers at or near theatrioventricular (AV) node in the right atrium (RA) to preservesynchronous ventricular depolarization without separate pacing in theRV. His-bundle pacing may provide a single-lead solution, sensing the RAand pacing the His bundle using a single lead in the RA, and activatingthe His bundle using a pulse configured to capture both of a His bundleand the local myocardium, or to capture the His bundle and not the localmyocardium.

Control

In an example, one or more of the specific patterns of longer andshorter AV delay period (e.g., 8 shortened AV delay interval beats then2 longer AV delay interval beats in a shortened AV delay period, etc.)of pacing-based or pattern-pacing-based HTN therapy, or the value of theAV delay intervals of the longer AV delay and the shortened AV delay,can be individually controlled, determined, or optimized for a specificpatient, using patient-specific physiologic information, such asdetected from the patient by one or more ambulatory medical devices. Inan example, the physiologic information can include a compositephysiological parameter, a stratifier configured to adjust the compositephysiologic parameter, or other physiologic information, including (orbased on) one or more heart sounds (e.g., one or more of S1-S4, etc.),impedance (e.g., thoracic impedance, etc.), or one or more otherphysiologic parameter, etc. Moreover, such previously determinedpatterns or values may change over time, and in certain examples, can beoptimized for specific time periods or other patterns, or triggered withrespect to one or more other physiologic information (e.g., sleep,exercise, time of day, etc.).

In an example, the device may evaluate the S1 and S2 response to aspecific pacing protocol to determine the value of the shorter andlonger AV delay intervals for a specific patient. In certain examples,the pacing protocol may involve testing a shortened AV delay intervalimmediately following an intrinsic beat and evaluating the S1 and S2changes during the shortened AV delay beat relative to the precedingintrinsic beat. Shortening of the AV delay is expected to increase S1and reduced S2 amplitudes. The value of the shortened AV delay can besuccessively reduced such that at each successive step transitions froman intrinsic beat to a progressively shorter AV delay as compared toprevious transition. An optimal shortened AV delay can include an AVdelay beyond which increase in S1 amplitude, or decrease in S2 amplitudeor both, relative to corresponding values during the preceding intrinsicbeat is similar to the changes during the previous transition to aslightly longer shortened AV delay. An optimal shortened AV delay caninclude an AV delay at which further reduction in AV delay are notexpected to cause further changes in heart sound based metrics (e.g., anincrease in S1 or decrease in S2, or both, etc.) relative to a precedingintrinsic beat (e.g., a point of diminishing returns).

Once the shortened AV delay is optimized, the pacing protocol can testmultiple options for longer AV delay. Each test can start from anintrinsic beat followed by 8-12 beats at the optimal shortened AV delayfollowed by 1-3 beats of one particular longer AV delay being evaluated.Various values of longer AV delay can be evaluated successively.Optimality of the longer AV delay can be determined using maximalreduction of S2 amplitude averaged over multiple beats 2-3 minutes fromthe initial intrinsic beat or minimal change in S2 amplitude (e.g.,averaged over multiple beats 2-3 minutes from the initial intrinsicbeat) from the first few shortened AV delay beat following the intrinsicbeat. Once the two AV delays are optimized, they can be used for theparticular subject until a need for re-optimization arises.

Further, S2 can be used to determine an optimal pattern during ashortened AV delay period. For example, after a transition from thelonger AV delay period to the shortened AV delay period, shortened AVdelay intervals can continue until S2 (or a composite value orstratifier including or based on S2) exceeds or increases above athreshold relative to an S2 value prior to transition (e.g., a relativechange, such as 20%, etc.), in certain examples in combination with aheart rate increase above a threshold relative to a heart rate prior totransition (e.g., a relative change, such as 20%, etc.), beforeinjecting 1-2 longer AV delay intervals. In an example, the number oflonger AV delay intervals can be determined using S2 information, heartrate information, or a combination of (or composite or stratifierincluding or based on) both. In the shortened AV delay period, longer AVdelay intervals can be periodically injected to keep the S2 information,heart rate information, or a combination of (or composite or stratifierincluding or based on) both, below one or more thresholds.

In an example, heart sound information may require signal averaging overseveral periods of a pattern (e.g., ensemble averaged heart sounds,etc.). In an example, the value of the AV delay intervals in the AVdelay periods can be separately averaged (e.g., for a longer AV delayperiod or a shortened AV delay period, etc.) across various overlapping,or non-overlapping timer periods.

In other examples, a cannon A wave (a RA/LA contraction against a closedtricuspid valve/mitral valve) can be detected using S1 information. Inan example, the shortened AV delay can be successively lowered until acannon A wave is detected. Once detected, the shortened AV delayinterval can be set as some percentage (e.g., 90%, etc.) of the cannon Awave value.

In other examples, the upper bound of the AV delay can be determinedusing a P wave of a cardiac signal and S4 information (e.g., a P-S4time). The shortened AV delay can be set as the determined upper bound(e.g., the P-S4 time). Further, as S4 can represent a mechanicalcontraction, the shortened AV delay can be set shorter than the upperbound of the AV delay, but longer than the end of S4 timing, so as notto affect atrial contraction.

In other examples, stroke impedance can be determined using a detectedimpedance. In certain examples, impedance information can be filteredfor respiration information, minute ventilation (MV) information, or oneor more other impedance measurements, depending on selected impedancevectors. In an example, a cardiac component of detected MV informationcan be used to confirm HS information, or can be used as an independentmetric. The shortened AV delay intervals can be reduced, and the longerAV delay intervals can be increased, e.g., until stroke impedance fallsbelow an absolute or relative threshold value, or until a furtherreduction in AV delay would no longer lead to any reduction in strokeimpedance (e.g., a point of diminishing returns).

Exercise Capacity and Tolerance

Shortening AV delay intervals to reduce filling and pressure may alsoreduce cardiac output, which can negatively impact exercise capacityand, in certain examples, patient tolerance to a provided therapy. Thepatient may feel the alternating patterns (e.g., a longer AV delayinterval versus a shortened AV delay interval, a transition back to thelonger AV delay interval from the shorter AV delay, etc.) of thepacing-based or pattern-pacing-based HTN therapy, and such feeling maybe unpleasant.

In an example, information from one or more sensors (e.g., impedance,respiration, activity, posture, etc.) can be used to adjust, reduce, ordiscontinue pacing-based or pattern-pacing-based HTN therapy based onpatient activity, exercise, or required cardiac output. If the patientis detected as active, therapy can be suspended or altered lessdrastically, such as to retain cardiac output.

In certain examples, if cardiac output is required, but heart rate doesnot rise, the vasculature of the heart can change, and the heart can tryto pump harder, which can be measured using heart sounds (e.g., S1, S2,etc.). If activity is detected and blood pressure increases (e.g., suchas indicated by heart sounds, etc.), but the heart rate does not rise(e.g., at the same time or to the same degree) with the detectedactivity, a pacing rate can be increased to improve cardiac output, incertain examples, separate from, or in combination with modulating of anAV delay or pacing pattern. Once activity is detected, an assessmentcircuit can switch modes, from pacing-based or pattern-pacing-based HTNtherapy mode to an activity mode, where an increased cardiac output isdesired. Once the activity mode is triggered, some hysteresis can berequired to transition back to the pacing-based or pattern-pacing-basedHTN therapy mode. In certain examples, no hysteresis is required totransition back to the activity mode.

In certain examples, an increase in heart sounds (e.g., S1-S4) can beused to adjust one or more of a pattern or an AV delay value. In anexample, information from one or more sensors (e.g., impedance,respiration, activity, posture, etc.) can be combined with heart soundsto control blood pressure control and exercise capacity.

In an example, the transition between the longer AV delay period and theshortened AV delay period can be gradual, stepping between the shortenedAV delay period and the longer AV delay period in a number of steps toreduce abrupt changes, and thereby reduce unpleasant sensationsassociated with abrupt changes in AV delay, and reducing the likelihoodfor baroreflex response. For example, the AV delay can be stepped downby a specific amount (e.g., 2 ms, 5 ms, 10 ms, etc.), in certainexamples, no more than a threshold amount each beat. In other examples,changes in AV delay intervals or the AV delay patterns can besynchronized, altered, or controlled with respect to a detectedrespiration cycle. For example, a heart rate can be driven up and an AVdelay interval can be increased during late inhalation, while, incontrast, the heart rate can be lowered and the AV delay interval can bedecreased during expiration.

Hypertension patients can be divided into different groups of overnightresponders: dippers and non-dippers. Many patients, when monitored forperiods 24-hours or longer, show lower blood pressure measurements atnight. Such patients are referred to as “dippers”. In contrast, patientsthat present constant or near-constant blood pressure measurements atday or night are referred to as “non-dippers”. Non-dippers generallyhave worse outcomes. In an example, pacing-based or pattern-pacing-basedHTN therapy can alter an AV delay or provide a pacing pattern configuredto promote a natural diurnal pattern, in certain examples, turning anon-dipper into a dipper. In other examples, a ventricle can be paced todetune the contraction, resulting a reduced cardiac output, which can beused to promote a natural diurnal pattern.

In an example, one or more sensors disclosed herein can be used todetermine if the patient is sleeping (e.g., activity sensor, posturesensor, etc.), such as to distinguish between daytime and nighttimeblood pressure measurements. In other examples, information about thesleep state of the patient can be received from the patient or acaregiver, such as at setup of the ambulatory medical device, orinformation about the sleep state of the patient can be assumed atspecific times of day, in certain examples confirmed using informationfrom the one or more sensors. In an example, the pacing-based orpattern-pacing-based HTN therapy can be more aggressive (e.g., longertime periods of (more) shortened AV delays, shorter AV delay values,etc.) when the patient is sleeping, inactive, or at rest, due to thedecrease in required patient cardiac output.

In certain examples, when a patient is detected as in atrialfibrillation (AF), altering a V-V pattern (e.g., in a ventricular rateregularization (VRR) mode of an ambulatory medical device) can alter ablood pressure in a patient. In other examples, information about heartsounds can be used to automatically adjust or optimize rate response ofa therapy. For example, if S1 (e.g., S1 amplitude, morphology, orenergy) increases at a given heart rate, the rate response factor of theVRR mode can be increased to increase heart rate. Similarly, to reduceheart rate, the rate response factor of the VRR mode can be decreased(e.g., to pace more intermittently).

In certain examples, an assessment circuit can propose changes to aclinician, for example, AV delay values, pacing patterns, pacing rateincreases, etc., as many times clinicians program devices tooconservatively. The proposed changes can enable a clinician to providepatient benefit they may not otherwise feel comfortable immediatelydoing so. The decrease in time to proper device programming can providea substantive benefit to the patient. In other examples, the assessmentcircuit can make changes to the programming of an ambulatory medicaldevice (e.g., within pre-approved safety bounds, etc.) configured toprovide a therapy to the patient.

Increased Pacing Rate

In certain examples, as AV delay intervals are shortened in pacing-basedor pattern-pacing-based HTN therapy, the pacing rate can be increased toaccount for the reduced cardiac output of the shortened AV delayintervals, separate from or in conjunction with detecting patientactivity. In an example, the pacing rate increases can be implementedwith each shortened AV delay intervals. In other examples, the pacingrate increases can be implemented with shortened AV delay intervals atspecific times (e.g., during activity, during the day, while moving ortaking steps, etc.) and not others (e.g., while inactive, sitting,sleeping, lying down, etc.).

In an example, the pacing rate increase can be implemented during someor all of each shortened AV delay period. In certain examples, thepacing rate can increase by a percentage, a threshold, or a set amount(e.g., 10%, 10-20 bpm, etc.). When increasing the pacing rate, one ormore physiologic parameters (e.g., heart sounds S1-S4, stroke volume,etc.), composite physiologic parameters, or stratifiers can be monitoredto ensure the cardiac output is increasing. As cardiac output (CO) isrelated to heart rate and stroke volume, care must be taken to ensurethat, as one parameter is changed, others behave as desired. In anexample, physiologic information from the patient can be used tomodulate the pacing rate increase, such as using heart sounds, cardiacelectrical activity, respiration information, impedance, activity, etc.The pacing rate changes can be abrupt, switching between rates, orgradual, stepping between rates so that the patient does not feel thetransitions.

In an example, in a pattern-pacing-based HTN therapy, including 8-12beats of shortened AV delay intervals interjected with 1-3 beats oflonger AV delay intervals, the pacing rate can either stay at theincreased value throughout the shortened AV delay period (including the1-3 beats of longer AV delay interval), transitioning back to theprevious pacing rate at the transition to the longer AV delay period, orthe pacing rate can modulate as the shortened AV delay intervals areinterjected with the longer AV delay intervals, with the ratetransitioning back or towards the previous rate at each interjectedlonger AV delay interval.

Control Parameters

In an example, once pattern-pacing therapy begins, a number ofconditions can be monitored, in conjunction with or separate from one ormore physiologic parameters from the patent.

At a first step, an assessment circuit can determine whether anarrhythmia is present, for example, using received physiologicinformation from the patient. The assessment circuit can monitor anatrial rate of the patient, as well as activity and respirationinformation (e.g., accelerometer signal and minute ventilation signal,such as using an impedance sensor, etc.).

At a second step, optionally concurrent with the first step, thepatterned-pacing therapy can be modulated using one or more physiologicparameters (e.g., heart sounds S1-S4, stroke volume, etc.), or one ormore composite physiologic parameters or stratifiers. In an example, theassessment circuit can recommend changes to one or more AV delayintervals (e.g., a shortened AV delay interval, a longer AV delayinterval, etc.), or moreover, can recommend a number of differentpatterns (e.g., X shortened AV delay intervals followed by Y longer AVdelay intervals, repeating with those or updated values, for a certaintime period, depending on the physiologic parameters or one or morecomposite physiologic parameters or stratifiers.

At a third step, optionally concurrent with one or more of the first andsecond steps, long-term safety monitoring or one or more otherconditions can be monitored (e.g., dyssynchrony, arrhythmia, exercise oractivity, etc.).

In an example, depending on the output of the first and second steps, ifnothing arises to cause concern, the first and second steps can loopwhile continuing to provide patterned-pacing therapy. At a fourth step,the pattern-pacing therapy is stopped, in certain examples, in responseto received physiologic information or because the therapy is complete.

FIG. 3 illustrates an example system (e.g., a medical device, etc.) 300including a signal receiver circuit 302 and an assessment circuit 304.The signal receiver circuit 302 can be configured to receive patientinformation, such as physiologic information of a patient (or group ofpatients) from one or more sensors. The assessment circuit 304 can beconfigured to receive information from the signal receiver circuit 302,and to determine one or more parameters (e.g., composite physiologicparameters, stratifiers, one or more pacing parameters, etc.), such asdescribed herein.

The assessment circuit 304 can be configured to provide an output to auser, such as to a display or one or more other user interface, theoutput including a score, a trend, or other indication. In otherexamples, the assessment circuit 304 can be configured to provide anoutput to another circuit, machine, or process, such as to control,adjust, or cease a therapy of a medical device, etc.

FIG. 4 illustrates an example system 400 including an ambulatory medicaldevice (AMD) 402 coupled to an external or remote system 404, such as anexternal programmer. In an example, the AMD 402 can be an implantabledevice, an external device, or a combination or permutation of one ormore implantable or external devices. In an example, one or more of thesignal receiver circuit 302 or the assessment circuit 304 can be locatedin the AMD 402, or the remote system 404. In an example, the AMD 402 caninclude a stimulation circuit configured to generate one or more pacingor defibrillation waveforms to be provided to a patient. The remotesystem 404 can include a specialized device configured to interact withthe AMD 402, including to program or receive information from the AMD402.

FIG. 5 illustrates an example of a Cardiac Rhythm Management (CRM)system 500 and portions of an environment in which the CRM system 500can operate. The CRM system 500 can include an ambulatory medicaldevice, such as an implantable medical device (IMD) 510 that can beelectrically coupled to a heart 505 such as through one or more leads508A-C coupled to the IMD 510 using a header 511, and an external system520 that can communicate with the IMD 510 such as via a communicationlink 503. The IMD 510 may include an implantable cardiac device such asa pacemaker, an implantable cardioverter-defibrillator (ICD), or acardiac resynchronization therapy defibrillator (CRT-D). The IMD 510 caninclude one or more monitoring or therapeutic devices such as asubcutaneously implanted device, a wearable external device, a neuralstimulator, a drug delivery device, a biological therapy device, or oneor more other ambulatory medical devices. The IMD 510 may be coupled to,or may be substituted by a monitoring medical device such as a bedsideor other external monitor.

As illustrated in FIG. 4, the IMD 510 can include a hermetically sealedcan 512 that can house an electronic circuit that can sense aphysiologic signal in the heart 505 and can deliver one or moretherapeutic electrical pulses to a target region, such as in the heart,such as through one or more leads 508A-C. In certain examples, the CRMsystem 500 can include only a single lead, such as 508B, or can includeonly two leads, such as 508A and 508B.

The lead 508A can include a proximal end that can be configured to beconnected to IMD 510 and a distal end that can be configured to beplaced at a target location such as in the right atrium (RA) 531 of theheart 505. The lead 508A can have a first pacing-sensing electrode 551that can be located at or near its distal end, and a secondpacing-sensing electrode 552 that can be located at or near theelectrode 551. The electrodes 551 and 552 can be electrically connectedto the IMD 510 such as via separate conductors in the lead 508A, such asto allow for sensing of the right atrial activity and optional deliveryof atrial pacing pulses. The lead 508B can be a defibrillation lead thatcan include a proximal end that can be connected to IMD 510 and a distalend that can be placed at a target location such as in the rightventricle (RV) 532 of heart 505. The lead 508B can have a firstpacing-sensing electrode 552 that can be located at distal end, a secondpacing-sensing electrode 553 that can be located near the electrode 552,a first defibrillation coil electrode 554 that can be located near theelectrode 553, and a second defibrillation coil electrode 555 that canbe located at a distance from the distal end such as for superior venacava (SVC) placement. The electrodes 552 through 555 can be electricallyconnected to the IMD 510 such as via separate conductors in the lead508B. The electrodes 552 and 553 can allow for sensing of a ventricularelectrogram and can optionally allow delivery of one or more ventricularpacing pulses, and electrodes 554 and 555 can allow for delivery of oneor more ventricular cardioversion/defibrillation pulses. In an example,the lead 508B can include only three electrodes 552, 554 and 555. Theelectrodes 552 and 554 can be used for sensing or delivery of one ormore ventricular pacing pulses, and the electrodes 554 and 555 can beused for delivery of one or more ventricular cardioversion ordefibrillation pulses. The lead 508C can include a proximal end that canbe connected to the IMD 510 and a distal end that can be configured tobe placed at a target location such as in a left ventricle (LV) 534 ofthe heart 505. The lead 508C may be implanted through the coronary sinus533 and may be placed in a coronary vein over the LV such as to allowfor delivery of one or more pacing pulses to the LV. The lead 508C caninclude an electrode 561 that can be located at a distal end of the lead508C and another electrode 562 that can be located near the electrode561. The electrodes 561 and 562 can be electrically connected to the IMD510 such as via separate conductors in the lead 508C such as to allowfor sensing of the LV electrogram and optionally allow delivery of oneor more resynchronization pacing pulses from the LV.

The IMD 510 can include an electronic circuit that can sense aphysiologic signal. The physiologic signal can include an electrogram ora signal representing mechanical function of the heart 505. Thehermetically sealed can 512 may function as an electrode such as forsensing or pulse delivery. For example, an electrode from one or more ofthe leads 508A-C may be used together with the can 512 such as forunipolar sensing of an electrogram or for delivering one or more pacingpulses. A defibrillation electrode from the lead 508B may be usedtogether with the can 512 such as for delivering one or morecardioversion/defibrillation pulses. In an example, the IMD 510 cansense impedance such as between electrodes located on one or more of theleads 508A-C or the can 512. The IMD 510 can be configured to injectcurrent between a pair of electrodes, sense the resultant voltagebetween the same or different pair of electrodes, and determineimpedance using Ohm's Law. The impedance can be sensed in a bipolarconfiguration in which the same pair of electrodes can be used forinjecting current and sensing voltage, a tripolar configuration in whichthe pair of electrodes for current injection and the pair of electrodesfor voltage sensing can share a common electrode, or tetrapolarconfiguration in which the electrodes used for current injection can bedistinct from the electrodes used for voltage sensing. In an example,the IMD 510 can be configured to inject current between an electrode onthe RV lead 508B and the can 512, and to sense the resultant voltagebetween the same electrodes or between a different electrode on the RVlead 508B and the can 512. A physiologic signal can be sensed from oneor more physiologic sensors that can be integrated within the IMD 510.The IMD 510 can also be configured to sense a physiologic signal fromone or more external physiologic sensors or one or more externalelectrodes that can be coupled to the IMD 510. Examples of thephysiologic signal can include one or more of heart rate, heart ratevariability, intrathoracic impedance, intracardiac impedance, arterialpressure, pulmonary artery pressure, RV pressure, LV coronary pressure,coronary blood temperature, blood oxygen saturation, one or more heartsounds, physical activity or exertion level, physiologic response toactivity, posture, respiration, body weight, or body temperature.

The arrangement and functions of these leads and electrodes aredescribed above by way of example and not by way of limitation.Depending on the need of the patient and the capability of theimplantable device, other arrangements and uses of these leads andelectrodes are.

The CRM system 500 can include a patient chronic condition-based HFassessment circuit, such as illustrated in the commonly assigned Qi Anet al., U.S. application Ser. No. 14/55,392, incorporated herein byreference in its entirety. The patient chronic condition-based HFassessment circuit can include a signal analyzer circuit and a riskstratification circuit. The signal analyzer circuit can receive patientchronic condition indicators and one or more physiologic signals fromthe patient, and select one or more patient-specific sensor signals orsignal metrics from the physiologic signals. The signal analyzer circuitcan receive the physiologic signals from the patient using theelectrodes on one or more of the leads 508A-C, or physiologic sensorsdeployed on or within the patient and communicated with the IMD 510. Therisk stratification circuit can generate a composite risk indexindicative of the probability of the patient later developing an eventof worsening of HF (e.g., an HF decompensation event) such as using theselected patient-specific sensor signals or signal metrics. The HFdecompensation event can include one or more early precursors of an HFdecompensation episode, or an event indicative of HF progression such asrecovery or worsening of HF status.

The external system 520 can allow for programming of the IMD 510 and canreceives information about one or more signals acquired by IMD 510, suchas can be received via a communication link 503. The external system 520can include a local external IMD programmer. The external system 520 caninclude a remote patient management system that can monitor patientstatus or adjust one or more therapies such as from a remote location.

The communication link 503 can include one or more of an inductivetelemetry link, a radio-frequency telemetry link, or a telecommunicationlink, such as an internet connection. The communication link 503 canprovide for data transmission between the IMD 510 and the externalsystem 520. The transmitted data can include, for example, real-timephysiologic data acquired by the IMD 510, physiologic data acquired byand stored in the IMD 510, therapy history data or data indicating IMDoperational status stored in the IMD 510, one or more programminginstructions to the IMD 510 such as to configure the IMD 510 to performone or more actions that can include physiologic data acquisition suchas using programmably specifiable sensing electrodes and configuration,device self-diagnostic test, or delivery of one or more therapies.

The patient chronic condition-based HF assessment circuit, or otherassessment circuit, may be implemented at the external system 520, whichcan be configured to perform HF risk stratification such as using dataextracted from the IMD 510 or data stored in a memory within theexternal system 520. Portions of patient chronic condition-based HF orother assessment circuit may be distributed between the IMD 510 and theexternal system 520.

Portions of the IMD 510 or the external system 520 can be implementedusing hardware, software, or any combination of hardware and software.Portions of the IMD 510 or the external system 520 may be implementedusing an application-specific circuit that can be constructed orconfigured to perform one or more particular functions, or can beimplemented using a general-purpose circuit that can be programmed orotherwise configured to perform one or more particular functions. Such ageneral-purpose circuit can include a microprocessor or a portionthereof, a microcontroller or a portion thereof, or a programmable logiccircuit, or a portion thereof. For example, a “comparator” can include,among other things, an electronic circuit comparator that can beconstructed to perform the specific function of a comparison between twosignals or the comparator can be implemented as a portion of ageneral-purpose circuit that can be driven by a code instructing aportion of the general-purpose circuit to perform a comparison betweenthe two signals. While described with reference to the IMD 510, the CRMsystem 500 could include a subcutaneous medical device (e.g.,subcutaneous ICD, subcutaneous diagnostic device), wearable medicaldevices (e.g., patch based sensing device), or other external medicaldevices.

FIG. 6 illustrates an example method 600 to determine an adjustedatrioventricular (AV) delay using determined first and secondphysiologic parameters. At 602, physiologic information is received froma patient, such as using a signal receiver circuit, or using one or moresensors, such as one or more sensors in, on, or associated with anambulatory medical device (AMD), during a first pacing period inresponse to pacing a heart of the patient at a first atrioventricular(AV) delay, and separately or distinctly, during a second pacing periodin response to pacing the heart of the patient at a second AV delay,different from the first AV delay.

At 604, a first physiologic parameter is determined using physiologicinformation received or sensed during the first pacing period. At 606, asecond physiologic parameter is determined using physiologic informationreceived or sensed during the second pacing period.

At 608, an adjusted AV delay can be determined for the first periodusing the first and second physiologic parameters. At 612, the first AVdelay can be adjusted using the first physiologic parameter. At 614, thesecond AV delay can be adjusted using the second physiologic parameter.In certain examples, one or both of the first and second parameters canbe used to adjust one or both of the first or second AV delay values. Incertain examples, an adjusted AV delay can be determined, but notadjusted. If the determined AV delay varies from an existing AV delay(e.g., by an absolute or relative threshold amount), a user can bealerted, or the determined AV delay value can be provided to the user.

FIG. 7 illustrates an example method 700 to determine a pacing periodusing received physiologic information. At 702, a first pacing waveformcan be generated (e.g., using a stimulation circuit) during a firstpacing period and a second pacing waveform can be generated during asecond pacing period. At 704, the first and second pacing periods can bealternated to provide pacing-based hypertension therapy to a heart of apatient to reduce patient blood pressure. The first pacing waveform canhave a first atrioventricular (AV) delay and the second pacing waveformcan have a second AV delay longer than the first AV delay.

At 706, physiologic information can be received from the patient, suchas using a signal receiver circuit. At 708, one of the first or secondpacing periods are determined for delivery to the patient using thereceived physiologic information.

At 710, the first or second pacing period can be adjusted using thereceived physiologic information. At 712, the first pacing period can bediscontinued or changed in response to a detected worsening patientcondition.

FIG. 8 illustrates an example method 800 to determine an adjustedpacing-based hypertension parameter using received patient metabolicdemand information. At 802, a first pacing waveform can be generated(e.g., using a stimulation circuit) during a first pacing period and asecond pacing waveform can be generated during a second pacing period.At 804, the first and second pacing periods can be alternated to providepacing-based hypertension therapy to a heart of a patient to reducepatient blood pressure. The first pacing waveform can have a firstatrioventricular (AV) delay and the second pacing waveform can have asecond AV delay longer than the first AV delay.

At 806, information can be received indicative of patient metabolicdemand (e.g., activity information, respiration information, postureinformation, etc.). At 808, an adjusted pacing-based hypertensionparameter can be determined using the received information indicative ofpatient metabolic demand.

At 810, an adjusted length (e.g., number of beats, etc.) of the first orsecond pacing period can be determined using the received informationindicative of patient metabolic demand. At 812, an adjusted AV delay(e.g., AV delay value) of the first pacing period can be determinedusing the received information indicative of patient metabolic demand.At 814, the first pacing period (e.g., having the shorter AV delay) canbe discontinued in response to the received information indicative ofpatient metabolic demand. For example, if periods of activity aredetected, the pacing-based hypertension therapy can be discontinued.

FIG. 9 illustrates an example method 900 to determine an increasedpacing rate for a pacing period using a first AV delay. At 902, a firstpacing waveform can be generated (e.g., using a stimulation circuit)during a first pacing period and a second pacing waveform can begenerated during a second pacing period. At 904, the first and secondpacing periods can be alternated to provide pacing-based hypertensiontherapy to a heart of a patient to reduce patient blood pressure. Thefirst pacing waveform can have a first atrioventricular (AV) delay andthe second pacing waveform can have a second AV delay longer than thefirst AV delay.

At 906, an increased pacing rate for the first pacing period can bedetermined using the first AV delay. If the first AV delay is adjusted,increased, or decreased, the pacing rate for the first pacing period canbe adjusted accordingly to increase cardiac output during the periods ofshorter AV delay values.

At 908, an adjusted AV delay for the first pacing waveform can bedetermined using received cardiac output information. At 910, anincreased pacing rate for the first pacing period can be determinedusing the adjusted AV delay.

In any one or more of the preceding examples, parameters can bedetermined, but not implemented. In certain examples, determinedparameters can be provided to a user, such as a clinician, to determinewhether or not to implement. In other examples, determined parameterscan be implemented once determined (e.g., if such changes fall withinestablished save zones, etc.). Further, such changes and determinationsprovide improvement to existing therapy devices, in certain examples,including the stimulation circuits, signal receiver circuits, orassessments circuits disclosed herein. Implementing therapy adjustments,or providing determined adjustments to a user for consideration, canspeed therapy or recovery time of a patient, such as by providingoptimized (or more optimized) therapy, or by reducing periods of lesseffective or ineffective therapy, extending the usable life of existingAMDs.

FIG. 10 illustrates a block diagram of an example machine 1000 uponwhich any one or more of the techniques (e.g., methodologies) discussedherein may perform. Portions of this description may apply to thecomputing framework of one or more of the medical devices describedherein, such as the IMD, the external programmer, etc.

Examples, as described herein, may include, or may operate by, logic ora number of components, or mechanisms in the machine 1000. Circuitry(e.g., processing circuitry) is a collection of circuits implemented intangible entities of the machine 1000 that include hardware (e.g.,simple circuits, gates, logic, etc.). Circuitry membership may beflexible over time. Circuitries include members that may, alone or incombination, perform specified operations when operating. In an example,hardware of the circuitry may be immutably designed to carry out aspecific operation (e.g., hardwired). In an example, the hardware of thecircuitry may include variably connected physical components (e.g.,execution units, transistors, simple circuits, etc.) including amachine-readable medium physically modified (e.g., magnetically,electrically, moveable placement of invariant massed particles, etc.) toencode instructions of the specific operation. In connecting thephysical components, the underlying electrical properties of a hardwareconstituent are changed, for example, from an insulator to a conductoror vice versa. The instructions enable embedded hardware (e.g., theexecution units or a loading mechanism) to create members of thecircuitry in hardware via the variable connections to carry out portionsof the specific operation when in operation. Accordingly, in an example,the machine-readable medium elements are part of the circuitry or arecommunicatively coupled to the other components of the circuitry whenthe device is operating. In an example, any of the physical componentsmay be used in more than one member of more than one circuitry. Forexample, under operation, execution units may be used in a first circuitof a first circuitry at one point in time and reused by a second circuitin the first circuitry, or by a third circuit in a second circuitry at adifferent time. Additional examples of these components with respect tothe machine 1000 follow.

In alternative embodiments, the machine 1000 may operate as a standalonedevice or may be connected (e.g., networked) to other machines. In anetworked deployment, the machine 1000 may operate in the capacity of aserver machine, a client machine, or both in server-client networkenvironments. In an example, the machine 1000 may act as a peer machinein peer-to-peer (P2P) (or other distributed) network environment. Themachine 1000 may be a personal computer (PC), a tablet PC, a set-top box(STB), a personal digital assistant (PDA), a mobile telephone, a webappliance, a network router, switch or bridge, or any machine capable ofexecuting instructions (sequential or otherwise) that specify actions tobe taken by that machine. Further, while only a single machine isillustrated, the term “machine” shall also be taken to include anycollection of machines that individually or jointly execute a set (ormultiple sets) of instructions to perform any one or more of themethodologies discussed herein, such as cloud computing, software as aservice (SaaS), other computer cluster configurations.

The machine (e.g., computer system) 1000 may include a hardwareprocessor 1002 (e.g., a central processing unit (CPU), a graphicsprocessing unit (GPU), a hardware processor core, or any combinationthereof), a main memory 1004, a static memory (e.g., memory or storagefor firmware, microcode, a basic-input-output (BIOS), unified extensiblefirmware interface (UEFI), etc.) 1006, and mass storage 1008 (e.g., harddrive, tape drive, flash storage, or other block devices) some or all ofwhich may communicate with each other via an interlink (e.g., bus) 1030.The machine 1000 may further include a display unit 1010, analphanumeric input device 1012 (e.g., a keyboard), and a user interface(UI) navigation device 1014 (e.g., a mouse). In an example, the displayunit 1010, input device 1012, and UI navigation device 1014 may be atouch screen display. The machine 1000 may additionally include a signalgeneration device 1018 (e.g., a speaker), a network interface device1020, and one or more sensors 1016, such as a global positioning system(GPS) sensor, compass, accelerometer, or one or more other sensors. Themachine 1000 may include an output controller 1028, such as a serial(e.g., universal serial bus (USB), parallel, or other wired or wireless(e.g., infrared (IR), near field communication (NFC), etc.) connectionto communicate or control one or more peripheral devices (e.g., aprinter, card reader, etc.).

Registers of the processor 1002, the main memory 1004, the static memory1006, or the mass storage 1008 may be, or include, a machine-readablemedium 1022 on which is stored one or more sets of data structures orinstructions 1024 (e.g., software) embodying or utilized by any one ormore of the techniques or functions described herein. The instructions1024 may also reside, completely or at least partially, within any ofregisters of the processor 1002, the main memory 1004, the static memory1006, or the mass storage 1008 during execution thereof by the machine1000. In an example, one or any combination of the hardware processor1002, the main memory 1004, the static memory 1006, or the mass storage1008 may constitute the machine-readable medium 1022. While themachine-readable medium 1022 is illustrated as a single medium, the term“machine-readable medium” may include a single medium or multiple media(e.g., a centralized or distributed database, and/or associated cachesand servers) configured to store the one or more instructions 1024.

The term “machine-readable medium” may include any medium that iscapable of storing, encoding, or carrying instructions for execution bythe machine 1000 and that cause the machine 1000 to perform any one ormore of the techniques of the present disclosure, or that is capable ofstoring, encoding or carrying data structures used by or associated withsuch instructions. Non-limiting machine-readable medium examples mayinclude solid-state memories, optical media, magnetic media, and signals(e.g., radio frequency signals, other photon based signals, soundsignals, etc.). In an example, a non-transitory machine-readable mediumcomprises a machine-readable medium with a plurality of particles havinginvariant (e.g., rest) mass, and thus are compositions of matter.Accordingly, non-transitory machine-readable media are machine-readablemedia that do not include transitory propagating signals. Specificexamples of non-transitory machine-readable media may include:non-volatile memory, such as semiconductor memory devices (e.g.,Electrically Programmable Read-Only Memory (EPROM), ElectricallyErasable Programmable Read-Only Memory (EEPROM)) and flash memorydevices; magnetic disks, such as internal hard disks and removabledisks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

The instructions 1024 may be further transmitted or received over acommunications network 1026 using a transmission medium via the networkinterface device 1020 utilizing any one of a number of transferprotocols (e.g., frame relay, internet protocol (IP), transmissioncontrol protocol (TCP), user datagram protocol (UDP), hypertext transferprotocol (HTTP), etc.). Example communication networks may include alocal area network (LAN), a wide area network (WAN), a packet datanetwork (e.g., the Internet), mobile telephone networks (e.g., cellularnetworks), Plain Old Telephone (POTS) networks, and wireless datanetworks (e.g., Institute of Electrical and Electronics Engineers (IEEE)802.11 family of standards known as Wi-Fi®, IEEE 802.16 family ofstandards known as WiMax®), IEEE 802.15.4 family of standards,peer-to-peer (P2P) networks, among others. In an example, the networkinterface device 1020 may include one or more physical jacks (e.g.,Ethernet, coaxial, or phone jacks) or one or more antennas to connect tothe communications network 1026. In an example, the network interfacedevice 1020 may include a plurality of antennas to wirelesslycommunicate using at least one of single-input multiple-output (SIMO),multiple-input multiple-output (MIMO), or multiple-input single-output(MISO) techniques. The term “transmission medium” shall be taken toinclude any intangible medium that is capable of storing, encoding orcarrying instructions for execution by the machine 1000, and includesdigital or analog communications signals or other intangible medium tofacilitate communication of such software. A transmission medium is amachine-readable medium.

Various embodiments are illustrated in the figures above. One or morefeatures from one or more of these embodiments may be combined to formother embodiments. Method examples described herein can be machine orcomputer-implemented at least in part. Some examples may include acomputer-readable medium or machine-readable medium encoded withinstructions operable to configure an electronic device or system toperform methods as described in the above examples. An implementation ofsuch methods can include code, such as microcode, assembly languagecode, a higher-level language code, or the like. Such code can includecomputer readable instructions for performing various methods. The codecan form portions of computer program products. Further, the code can betangibly stored on one or more volatile or non-volatilecomputer-readable media during execution or at other times.

The above detailed description is intended to be illustrative, and notrestrictive. The scope of the disclosure should, therefore, bedetermined with references to the appended claims, along with the fullscope of equivalents to which such claims are entitled.

What is claimed is:
 1. A system comprising: a stimulation circuitconfigured to generate a first pacing waveform first and second pacingwaveforms; a signal receiver circuit configured to receive physiologicinformation from the patient, and an assessment circuit configured tocontrol generation of the first and second pacing waveforms to providepatterned-pacing-based hypertension therapy to a heart of a patient,including to control generation of the first pacing waveform having afirst atrioventricular (AV) delay during a first pacing period to reducepatient blood pressure and the second pacing waveform having a second AVdelay, longer than the first AV delay, to prevent an increase in patientblood pressure during a second pacing period, and to dynamicallyalternate the first and second pacing periods, based on the receivedphysiologic information, to provide a dynamic pattern of first andsecond pacing waveforms to reduce patient blood pressure.
 2. The systemof claim 1, wherein the assessment circuit is configured to adjust thefirst or second pacing period using the received physiologicinformation.
 3. The system of claim 1, wherein the assessment circuit isconfigured to detect a patient condition using the received physiologicinformation, and wherein to dynamically alternate the first and secondpacing periods includes to reduce the first pacing period with respectto the second pacing period in response to a detected worsening patientcondition.
 4. The system of claim 3, wherein the assessment circuit isconfigured to detect an arrhythmia of the patient using the receivedphysiologic information, and wherein to dynamically alternate the firstand second pacing periods includes to reduce the first pacing periodwith respect to the second pacing period in response to a number ofdetected arrhythmias over a threshold time period.
 5. The system ofclaim 1, wherein the assessment circuit is configured to determine anarrhythmia metric of the patient using the received physiologicinformation, and to dynamically alternate the first and second pacingperiods using the determined arrhythmia metric.
 6. The system of claim1, wherein the assessment circuit is configured to determine a heartfailure metric of the patient using the received physiologicinformation, and to dynamically alternate the first and second pacingperiods using the determined heart failure metric.
 7. The system ofclaim 1, wherein the signal receiver circuit is configured to receivethird heart sound (S3) information and fourth heart sound (S4)information from the patient, and wherein the assessment circuit isconfigured to determine an indication of early-to-lateventricular-filling velocities (E/A ratio) using the S3 information andthe S4 information, and to dynamically alternate the first and secondpacing periods using the determined E/A ratio.
 8. The system of claim 1,wherein the signal receiver circuit is configured to receive first heartsound (S1) information from the patient, and wherein the assessmentcircuit is configured to determine an indication of long-term impact ofthe first pacing period to the patient using S1 information detectedduring the second pacing period, and to dynamically alternate the firstand second pacing periods using the determined indication of long-termimpact.
 9. The system of claim 1, wherein the signal receiver circuit isconfigured to receive first heart sound (S1) information and secondheart sound (S2) information from the patient, and wherein theassessment circuit is configured to determine an S1 metric and an S2metric for the patient over the first and second pacing periods, and toadjust the first or second pacing periods to reduce the S2 metricwithout reducing the S1 metric.
 10. The system of claim 1, wherein theassessment circuit is configured to, in response to the determined firstor second pacing period, provide an indication to a user to adjust thepacing-based hypertension therapy to the patient.
 11. At least onenon-transitory machine-readable medium including instructions that, whenperformed by a medical device, cause the medical device to: generate afirst pacing waveform during a first pacing period and a second pacingwaveform during a second pacing period to provide pacing-basedhypertension therapy to a heart of a patient to reduce patient bloodpressure, wherein the first pacing waveform has a first atrioventricular(AV) delay to reduce patient blood pressure and the second pacingwaveform has a second AV delay longer than the first AV delay to preventan increase in patient blood pressure during the second pacing period;receive physiologic information from the patient; and dynamicallyalternate the first and second pacing periods, based on the receivedphysiologic information, to provide a dynamic pattern of first andsecond pacing waveforms to reduce patient blood pressure.
 12. The atleast one machine-readable medium of claim 11, wherein the instructions,when performed by the medical device, cause the medical device to:adjust the first or second pacing period using the received physiologicinformation.
 13. The at least one machine-readable medium of claim 11,wherein the instructions, when performed by the medical device, causethe medical device to: detect a patient condition using the receivedphysiologic information, wherein to dynamically alternate the first andsecond pacing periods includes to reduce the first pacing period withrespect to the second pacing period in response to a detected worseningpatient condition.
 14. The at least one machine-readable medium of claim11, wherein the instructions, when performed by the medical device,cause the medical device to: detect an arrhythmia of the patient usingthe received physiologic information, wherein to dynamically alternatethe first and second pacing periods includes to reduce the first pacingperiod with respect to the second pacing period in response to a numberof detected arrhythmias over a threshold time period.
 15. The at leastone machine-readable medium of claim 11, wherein the instructions, whenperformed by the medical device, cause the medical device to: determinean arrhythmia metric of the patient using the received physiologicinformation, and to adjust the first or second pacing period using thedetermined arrhythmia metric.
 16. A method comprising: generating, usinga stimulation circuit, a first pacing waveform during a first pacingperiod and a second pacing waveform during a second pacing period toprovide pacing-based hypertension therapy to a heart of a patient toreduce patient blood pressure, wherein the first pacing waveform has afirst atrioventricular (AV) delay to reduce patient blood pressure andthe second pacing waveform has a second AV delay longer than the firstAV delay to prevent an increase in patient blood pressure during thesecond pacing period; receiving, using a signal receiver circuit,physiologic information from the patient; and dynamically alternatingthe first and second pacing periods, based on the received physiologicinformation, to provide a dynamic pattern of first and second pacingwaveforms to reduce patient blood pressure.
 17. The method of claim 16,including: adjusting, using the assessment circuit, the first or secondpacing period using the received physiologic information.
 18. The methodof claim 16, including: detecting, using the assessment circuit, apatient condition using the received physiologic information,dynamically alternating the first and second pacing periods includesreducing the first pacing period with respect to the second pacingperiod in response to a detected worsening patient condition.
 19. Themethod of claim 18, including: detecting, using the assessment circuit,an arrhythmia of the patient using the received physiologic information,wherein dynamically alternating the first and second pacing periodsincludes reducing the first pacing period with respect to the secondpacing period in response to a number of detected arrhythmias over athreshold time period.
 20. The method of claim 16, including:determining, using the assessment circuit, an arrhythmia metric of thepatient using the received physiologic information; and adjusting, usingthe assessment circuit, the first or second pacing period using thedetermined arrhythmia metric.